Current Neuropharmacology - Volume 18, Issue 11, 2020

Until recently, it was thought that there were no lymphatic vessels in the central nervous system (CNS). Therefore, all metabolic processes were assumed to take place only in the circulation of the cerebrospinal fluid (CSF) and through the blood-brain barrier’s (BBB), which regulate ion transport and ensure the functioning of the CNS. However, recent findings yield a new perspective: There is an exchange of CSF with interstitial fluid (ISF), which is drained to the paravenous space and reaches lymphatic nodes at the end. This circulation is known as the glymphatic system. The glymphatic system is an extensive network of meningeal lymphatic vessels (MLV) in the basal area of the skull that provides another path for waste products from CNS to reach the bloodstream. MLV develop postnatally, initially appearing around the foramina in the basal part of the skull and the spinal cord, thereafter sprouting along the skull’s blood vessels and spinal nerves in various areas of the meninges. VEGF-C protein (vascular endothelial growth factor), expressed mainly by vascular smooth cells, plays an important role in the development of the MLV. The regenerative potential and plasticity of MLV and the novel discoveries related to CNS drainage offer potential for the treatment of neurodegenerative diseases such as dementia, hydrocephalus, stroke, multiple sclerosis, and Alzheimer disease (AD). Herein, we present an overview of the structure and function of the glymphatic system and MLV, and their potential involvement in the pathology and progression of neurodegenerative diseases.

Background: Atherosclerosis is a chronic inflammatory condition that affects different arteries in the human body and often leads to severe neurological complications, such as stroke and its sequelae. Affected blood vessels develop atherosclerotic lesions in the form of focal thickening of the intimal layer, so called atherosclerotic plaques. Objectives: Despite the high priority of atherosclerosis research for global health and the numerous preclinical and clinical studies conducted, currently, there is no effective pharmacological treatment that directly impacts atherosclerotic plaques. Many knowledge gaps exist in our understanding of the mechanisms of plaque formation. In this review, we discuss the role of mitochondria in different cell types involved in atherogenesis and provide information about mtDNA mutations associated with the disease. Results: Mitochondria of blood and arterial wall cells appear to be one of the important factors in disease initiation and development. Significant experimental evidence connects oxidative stress associated with mitochondrial dysfunction and vascular disease. Moreover, mitochondrial DNA (mtDNA) deletions and mutations are being considered as potential disease markers. Further study of mtDNA damage and associated dysfunction may open new perspectives for atherosclerosis treatment. Conclusion: Mitochondria can be considered as important disease-modifying factors in several chronic pathologies. Deletions and mutations of mtDNA may be used as potential disease markers. Mitochondria-targeting antioxidant therapies appear to be promising for the development of treatment of atherosclerosis and other diseases associated with oxidative stress and chronic inflammation.

Accumulative evidence has shown that mitochondrial dysfunction plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial impairment actively contributes to the synaptic and cognitive failure that characterizes AD. The presence of soluble pathological forms of tau like hyperphosphorylated at Ser396 and Ser404 and cleaved at Asp421 by caspase 3, negatively impacts mitochondrial bioenergetics, transport, and morphology in neurons. These adverse effects against mitochondria health will contribute to the synaptic impairment and cognitive decline in AD. Current studies suggest that mitochondrial failure induced by pathological tau forms is likely the result of the opening of the mitochondrial permeability transition pore (mPTP). mPTP is a mitochondrial mega-channel that is activated by increases in calcium and is associated with mitochondrial stress and apoptosis. This structure is composed of different proteins, where Ciclophilin D (CypD) is considered to be the primary mediator of mPTP activation. Also, new studies suggest that mPTP contributes to Aβ pathology and oxidative stress in AD. Further, inhibition of mPTP through the reduction of CypD expression prevents cognitive and synaptic impairment in AD mouse models. More importantly, tau protein contributes to the physiological regulation of mitochondria through the opening/interaction with mPTP in hippocampal neurons. Therefore, in this paper, we will discuss evidence that suggests an important role of pathological forms of tau against mitochondrial health. Also, we will discuss the possible role of mPTP in the mitochondrial impairment produced by the presence of tau pathology and its impact on synaptic function present in AD.

Traumatic injury to the spinal cord (SCI) and brain (TBI) are serious health problems and affect many people every year throughout the world. These devastating injuries are affecting not only patients but also their families socially as well as financially. SCI and TBI lead to neurological dysfunction besides continuous inflammation, ischemia, and necrosis followed by progressive neurodegeneration. There are well-established changes in several other processes such as gene expression as well as protein levels that are the important key factors to control the progression of these diseases. We are not yet able to collect enough knowledge on the underlying mechanisms leading to the altered gene expression profiles and protein levels in SCI and TBI. Cell loss is hastened by the induction or imbalance of pro- or anti-inflammatory expression profiles and transcription factors for cell survival after or during trauma. There is a sequence of events of dysregulation of these factors from early to late stages of trauma that opens a therapeutic window for new interventions to prevent/ restrict the progression of these diseases. There has been increasing interest in the modulation of these factors for improving the patient’s quality of life by targeting both SCI and TBI. Here, we review some of the recent transcriptional factors and protein biomarkers that have been developed and discovered in the last decade in the context of targeted therapeutics for SCI and TBI patients.

Background: The only conclusive way to diagnose Alzheimer’s is to carry out brain autopsy of the patient’s brain tissue and ascertain whether the subject had Alzheimer’s or any other form of dementia. However, due to the non-feasibility of such methods, to diagnose and conclude the conditions, medical practitioners use tests that examine a patient’s mental ability. Objective: Accurate diagnosis at an early stage is the need of the hour for initiation of therapy. The cause for most Alzheimer’s cases still remains unknown except where genetic distinctions have been observed. Thus, a standard drug regimen ensues in every Alzheimer’s patient, irrespective of the cause, which may not always be beneficial in halting or reversing the disease progression. To provide a better life to such patients by suppressing existing symptoms, early diagnosis, curative therapy, site-specific delivery of drugs, and application of hyphenated methods like artificial intelligence need to be brought into the main field of Alzheimer’s therapeutics. Methods: In this review, we have compiled existing hypotheses to explain the cause of the disease, and highlighted gene therapy, immunotherapy, peptidomimetics, metal chelators, probiotics and quantum dots as advancements in the existing strategies to manage Alzheimer’s. Conclusion: Biomarkers, brain-imaging, and theranostics, along with artificial intelligence, are understood to be the future of the management of Alzheimer’s.

Epilepsy is a devastating neurological condition characterized by long-term tendency to generate unprovoked seizures, affecting around 1-2 % of the population worldwide. Epilepsy is a serious health concern which often associates with other neurobehavioral comorbidities that further worsen disease conditions. Despite tremendous research, the mainstream anti-epileptic drugs (AEDs) exert only symptomatic relief leading to 30% of untreatable patients. This reflects the complexity of the disease pathogenesis and urges the precise understanding of underlying mechanisms in order to explore novel therapeutic strategies that might alter the disease progression as well as minimize the epilepsy-associated comorbidities. Unfortunately, the development of novel AEDs might be a difficult process engaging huge funds, tremendous scientific efforts and stringent regulatory compliance with a possible chance of end-stage drug failure. Hence, an alternate strategy is drug repurposing, where anti-epileptic effects are elicited from drugs that are already used to treat non-epileptic disorders. Herein, we provide evidence of the anti-epileptic effects of Fingolimod (FTY720), a modulator of sphingosine-1-phosphate (S1P) receptor, USFDA approved already for Relapsing-Remitting Multiple Sclerosis (RRMS). Emerging experimental findings suggest that Fingolimod treatment exerts disease-modifying anti-epileptic effects based on its anti-neuroinflammatory properties, potent neuroprotection, anti-gliotic effects, myelin protection, reduction of mTOR signaling pathway and activation of microglia and astrocytes. We further discuss the underlying molecular crosstalk associated with the anti-epileptic effects of Fingolimod and provide evidence for repurposing Fingolimod to overcome the limitations of current AEDs.

Modern times have seen depression and cardiovascular disease (CVD) become notorious public health concerns, corresponding to alarming proportions of morbidity, mortality, decreased quality of life, and economic costs. Expanding comprehension of the pathogenesis of depression as an immunometabolic disorder has identified numerous pathophysiologic phenomena in common with CVD, including chronic inflammation, insulin resistance, and oxidative stress. These shared components could be exploited to offer improved alternatives in the joint management of these conditions. Abundant preclinical and clinical data on the impact of established treatments for CVD in the management of depression have allowed for potential candidates to be proposed for the joint management of depression and CVD as immunometabolic disorders. However, a large proportion of the clinical investigation currently available exhibits marked methodological flaws which preclude the formulation of concrete recommendations in many cases. This situation may be a reflection of pervasive problems present in clinical research in psychiatry, especially pertaining to study homogeneity. Therefore, further high-quality research is essential in the future in this regard.

Peripheral nerve injuries (PNIs) are accompanied with neuropathic pain and functional disability. Despite improvements in surgical repair techniques in recent years, the functional recovery is yet unsatisfied. Indeed a successful nerve repair depends not only on the surgical strategy but also on the cellular and molecular mechanisms involved in traumatic nerve injury. In contrast to all strategies suggested for nerve repair, pharmacotherapy is a cheap, accessible and non-invasive treatment that can be used immediately after nerve injury. This study aimed to review the effects of some pharmacological agents on the nerve regeneration after traumatic PNI evaluated by functional, histological and electrophysiological assessments. In addition, some cellular and molecular mechanisms responsible for their therapeutic actions, restricted to neural tissue, are suggested. These findings can not only help to find better strategies for peripheral nerve repair, but also to identify the neuropathic effects of various medications and their mechanisms of action.